The present invention relates to a process for preparing a polymer composition containing a physiologically active substance. More particularly, the present invention relates to a process for preparing a polymer composition containing a physiologically active substance and having the property of releasing the active substance at the controlled rate.
In one aspect, the present invention relates to a process for preparing a polymer composition containing a physiologically active substance and having the property of eluting the active substance at the rate controlled by pH.
In another aspect, the present invention relates to a process for preparing a polymer composition comprising a spherical polymer matrix of 50 to 5,000.mu. in size containing a physiologically active substance and having the property of releasing the active substance at the controlled rate.
Various compounds having physiological activities have been broadly utilized in various fields including medical science, agriculture and engineering, and these compounds have proved to be indispensable in industry and living in many ways. Many physiologically active substances, without distinction of inorganic substance and organic substance, or low molecular compound and high molecular compound, have been known and even now are being developed. However, in the utilization of these active substances, some common defects and inconveniences have been found. One of them is a fact that in general these physiologically active substances are effective only within a certain range of concentration in an environment in which they act, but they are not only ineffective in an concentration below such appropriate range but also often bring about harmful side reactions or side effects when they exceed the concentration range. However, on the other hand, in order to keep such organic substances continuously within the appropriate concentration range, they must be continuously replenished at an appropriate rate because they are consumed or spent simultaneously with fulfilling their function. Although there is a method of supplying or replenishing the desired substance continuously at an appropriate rate by using an apparatus or machine, the most convenient method which can be carried out in any environment and in any place is such a method that sufficient amount of the desired substance is previously contained in a certain supporting carrier so that the substance is naturally released from the carrier at the desired rate depending on the structure and function or carrier. Second, many physiologically active substances are easy to suffer a change such as deterioration and decomposition caused by various factors in an environment in which they are maintained or act, before their function is fulflled. Therefore, it is necessary to maintain these active substances in a protected stable state until their desired function is displayed and, in this sense, it is desirable for efficiently utilizing the active substances to stabilize them by maintaining in an appropriate supporting carrier.
Mainly, for the reason as described above, such a method as containing or adsorbing various physiologically active substances in or onto an appropriate supporting carrier for use has recently come to be studied extensively. A high polymer is one of the most desirable materials as such supporting carrier. The reason is that the high polymer is a high molecular weight compound in which the desired physiologically active substance can be easily caught and maintained within the molecular structure of the compound, that the releasing rate of the desired substance can be easily controlled by adjusting the structure and shape of the polymer by means of the polymer chemical technique, and that in many cases the high polymer is physiologically neutral as a carrier so that it has no physiological effects on environment.
Therefore, the problem is now how to include or support the desired substance in a high polymer carrier in such a state that the substance can be easily released at the desired rate as described above with the original properties being not harmed.
Heretofore, high polymer materials used as a pharmaceutical additive are generally a polymer such as, for example polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl acetate, methyl cellulose, methacrylate-methacrylic acid-methyl methacrylate copolymer, methylacrylate-methacrylic acid copolymer and styrene-maleic acid copolymer. In case of mixing these polymers and medicine to form a tablet, etc., a large amount of organic solvent is required for dissolving the polymer. Such organic solvent includes chloroform-ethanol, methanol-ethylacetate, cyclohexane, acetone, ethanol, water, etc. However, these organic solvents other than ethanol and water will remain as a trace within the matrix even if the degassing treatment is apparently sufficiently carried out. In case of continuous administration of medicine over a long period, the side effect due to the cumulative build-up thereof becomes a problem. Alternatively, in case of preparing preparations which release gradually an effective ingredient contained therein (hereinafter referred to "a controlled releasing agent") in a form of tablet, film, particle, powder etc. by mixing a polymerizable monomer, a catalyst for polymerization of monomer and medicine, the following defects are noted:
(1) The reaction temperature must be raised to near 80.degree. C. for polymerizing the monomer, and consequently the distribution state of medicine in the interior of matrix becomes not uniform and the medicine is deteriorated with high temperature; PA0 (2) The catalyst remaining in the interior of the matrix cannot be thoroughly removed; and PA0 (3) The cost is high because it takes a few days to complete the reaction. PA0 (1) Since many physiologically active substances have a physiological activity owing to their peculiar molecular structure, it is not desirable to expose them to such a state as being contacted with other chemicals at comparatively elevated temperatures. In this regard, it is considered to be advantageous to contain them in a high polymer carrier at a lower temperature as far as possible; PA0 (2) In order to adjust the structure of carrier so that the desired substance is contained in the carrier sufficiently uniformly and released therefrom at an appropriate rate, the method of mixing a high polymer carrier in a monomeric state before polymerization with the desired substance and polymerizing the mixture to contain the desired substance into the carrier is excellent; and PA0 (3) It is necessary to impart the polymer such as internal porous structure or a structure having broad surface area that the desired substance can be appropriately released, and it is advantageous to design a structure and shape of polymer starting from the monomer. PA0 (1) A polymerizable monomer and a physiologically active substance and/or a non-polymerizable compound (i.e. crystallizable compound) which is insoluble or soluble in the monomer and freezes at low temperatures to be crystallized or is a crystal at room temperature are mixed to prepare a solution or suspension; PA0 (2) A polymerizable monomer and a physiologically active substance are mixed, and the mixture is added to a medium insoluble in the polymerizable monomer with or without adding an appropriate medium to prepare a microsphere comprising the polymerizable monomer and the physiological active substance, which is then separated from the medium; and PA0 (3) A polymerizable monomer is cast to a film and a physiologically active substance or a polymerizable monomer containing it and an insoluble medium are flowed on the surface thereof to prepare a monomer film having dispersed physiologically active substance on the surface.
For example, in a case, it takes 3 days to prepare a controlled releasing agent by polymerizing 2-hydroxyethyl methacrylate and ethylene glycol dimethacrylate containing norethandrolene in the presence of t-butylperoctanoate as a catalyst under a nitrogen atmosphere at 80.degree. C. (U.S. Ser. No. 766,840 filed Oct. 11, 1968). In another example, a controlled releasing agent is prepared by polymerizing a polymerizable monomer in the presence of catalyst, impregnating the polymer obtained with a solution containing a medicine to permeate it into the interior of the matrix of polymer and drying. However, in the agent so obtained the catalyst is not removed from the matrix and it is difficult to contain a large amount of medicine per unit volume of matrix depending on the hydrophilic nature of matrix. Further, in another case a controlled releasing agent is prepared by polymerising a mixture of Cab-O-Sil EH5(RTM) and 2-hydroxyethyl methacrylate, N-vinyl-2-pyrrolidone, methyl methacrylate, divinyl benzene and t-butylperoctanoate under a nitrogen atmosphere at 54.degree. C. for 12 hours and immersing the polymer matrix obtained into a NaCl aqueous solution containing methantheline bromide to impregnate methantheline bromide in the interior of matrix (U.S. Ser. Nos. 39,668; 395,492; 395,691; 395,695 all were filed July 6, 1982). However, this process comprises two steps two steps of polymerization and impregnation of medicine, and so it is expensive.
As a result of studying on these points the present inventors have come to the following conclusion:
The present invention has been accomplished on the basis of the principle and facts as described above.